Dataset Information

Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo.

ABSTRACT: A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses encode FLIP proteins, homologous to cFLIPshort, which are described to regulate Caspase-8 and the host cell death machinery. In the current study a mouse model was generated to show the impact of viral FLIP (vFLIP) from Kaposi's Sarcoma-associated Herpesvirus (KSHV)/ Human Herpesvirus-8 (HHV-8) on cell death regulation in the gut. Our results demonstrate that expression of vFlip in intestinal epithelial cells suppressed cFlip expression, but protected mice from lethality, tissue damage and excessive apoptotic cell death induced by genetic cFlip deletion. Finally, our model shows that vFlip expression decreases cFlip mediated Caspase-8 activation in intestinal epithelial cells. In conclusion, our data suggests that viral FLIP neutralizes and compensates for cellular FLIP, efficiently counteracting host cell death induction and facilitating further propagation in the host organism.

SUBMITTER: Ruder B

PROVIDER: S-EPMC6992192 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo.

Ruder Barbara B Günther Claudia C Stürzl Michael M Neurath Markus Friedrich MF Cesarman Ethel E Ballon Gianna G Becker Christoph C

PloS one 20200130 1

A strict cell death control in the intestinal epithelium is indispensable to maintain barrier integrity and homeostasis. In order to achieve a balance between cell proliferation and cell death, a tight regulation of Caspase-8, which is a key player in controlling apoptosis, is required. Caspase-8 activity is regulated by cellular FLIP proteins. These proteins are expressed in different isoforms (cFLIPlong and cFLIPshort) which determine cell death and survival. Interestingly, several viruses enc ...[more]

PMID: 31999759

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Project description:Apoptosis and efficient efferocytosis are integral to growth, development, and homeostasis. The heterogeneity of these mechanisms in different cells across distinct tissues renders it difficult to develop broadly applicable in vivo technologies. Here, we introduced a novel inducible caspase-9 (iCasp9) mouse model which allowed targeted cell apoptosis and further facilitated investigation of concomitant efferocytosis. We generated iCasp9+/+ mice with conditional expression of chemically inducible caspase-9 protein that is triggered in the presence of Cre recombinase. In vitro, bone marrow cells from iCasp9+/+ mice showed expression of the iCasp9 protein when transduced with Cre-expressing adenovirus. Treatment of these cells with the chemical dimerizer (AP20187/AP) resulted in iCasp9 processing and cleaved caspase-3 upregulation, indicating successful apoptosis induction. The in vivo functionality and versatility of this model was demonstrated by crossing iCasp9+/+ mice with CD19-Cre and Osteocalcin (OCN)-Cre mice to target CD19+ B cells or OCN+ bone-lining osteoblasts. Immunofluorescence and/or immunohistochemical staining in combination with histomorphometric analysis of EGFP, CD19/OCN, and cleaved caspase-3 expression demonstrated that a single dose of AP effectively induced apoptosis in CD19+ B cells or OCN+ osteoblasts. Examination of the known efferocytes in the target tissues showed that CD19+ cell apoptosis was associated with infiltration of dendritic cells into splenic B cell follicles. In the bone, where efferocytosis remains under-explored, the use of iCasp9 provided direct in vivo evidence that macrophages are important mediators of apoptotic osteoblast clearance. Collectively, this study presented the first mouse model of iCasp9 which achieved selective apoptosis, allowing examination of subsequent efferocytosis. Given its unique feature of being controlled by any Cre-expressing mouse lines, the potential applications of this model are extensive and will bring forth more insights into the diversity of mechanisms and cellular effects induced by apoptosis including the physiologically important efferocytic process that follows.

Dataset Information

Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo.

Publications

Viral FLIP blocks Caspase-8 driven apoptosis in the gut in vivo.

Similar Datasets

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